This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Aging causes a decline in cell-mediated immunity (CMI) and is associated with a tremendous increase in the late-life morbidity from influenza infections. Vaccination can prevent influenza illness but current vaccines are only 50-60% effective in the over 65 population (versus 90% in younger adults). Even with this limited efficacy, influenza vaccination is a cost-saving intervention due to the reduction in hospitalization for acute respiratory illness and congestive heart failure (CHF). This proposal outlines a strategy to advance the basic science of influenza learned from studies in the aged mouse model, to application in a very high-risk population of older adults with CHF. Identifying age and CHF-related changes in the innate and adaptive immune responses to influenza and influenza vaccination, is imperative to the development of new vaccines or adjuvant therapies for improved prophylaxis in older people. The long-range goal of this project is to use translational methodology to determine the mechanism by which age and disease-related factors increase the risk of influenza and diminish vaccine efficacy. The objective of this application is to characterize protective immunologic responses, compare the level of immunity in different risk groups, and finally define the level of laboratory measures that predict outcomes of illness in older people. In the process, clinical and laboratory measures will be developed as individual and population indicators of how risk for influenza illness is altered by vaccination and including clinical trials of new vaccines. The central hypothesis of the application is that the level of granzyme B (Grz B) in influenza-specific cytotoxic T lymphocytes (CTL) predicts risk for influenza illness. Grz B levels decrease with advancing age and functional decline due to a dysregulation of T-cell function that is not reversed by vaccination with killed influenza virus. The rationale for the proposal is that older adults with CHF have a very high-risk for serious complications of influenza and suggests that the senescent immune response to influenza is further compromised in the presence of CHF. Influenza attack rates are higher and vaccine efficacy is lower in this population. CHF in older adults thus provides a model for studying immunologic responsiveness that can be linked to clinical outcomes. Very high-risk groups of older adults who continue to suffer disabling consequences of influenza due to poor responses to current killed-virus vaccines can then be targeted for new prophylaxis strategies. Recent studies have highlighted the role of Toll-like receptors (TLR) in the transition from innate to adaptive immune responses. TLR recognize pathogen-associated molecular patterns (PAMP) and stimulate cytokine production by a number of cells including Th type 1 (Th1), creating the necessary microenvironment to stimulate effector mechanisms such as CTL. In viral infections, it is critical that the transition from the innate to adaptive immune response activates cytotoxic T-lymphocytes (CTL) to kill virus-infected host cells. The methodology derived from this work will be critical for screening new vaccines for immunologic responsiveness prior to expensive, large clinical trials. In the interim, it will be possible to combine vaccination with the use of antiviral drugs in those very high-risk groups with poor responses to current vaccines.
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